Random alkylene oxide copolymers for medical and surgical utilities

ABSTRACT

Medical and surgical uses for random alkylene oxide copolymers have been discovered. Preferably, this is a biocompatible, non-metabolizable, non-toxic, and/or readily eliminated compound that has a viscosity which is adjustable for different utilities (e.g., from runny oil to thick grease). It is also preferable to formulate the compound as an anhydrous and/or flowable liquid before use or further formulation.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of provisional U.S. Patent Appln.No. 60/446,534, filed Feb. 12, 2003; it is also related to the patentapplication (atty. dkt. 4278-4) entitled “Random and Non-Random AlkyleneOxide Polymer Alloy Compositions” and being filed on Feb. 12, 2004. Bothapplications are incorporated by reference.

FIELD OF THE INVENTION

The invention relates to medical and surgical uses of a random alkyleneoxide copolymer.

BACKGROUND OF THE INVENTION

In the medical and surgical fields, there has been an unmet need forcompounds with handling characteristics that range from a viscous oil toa hard wax. Desirable compounds would have one or more of the followingproperties: biocompatibility, stability during storage and underphysiological conditions, low toxicity and corrosiveness, readilyeliminated from the body in unmodified form, easy and inexpensive tomanufacture and store, and variable viscosity and hardness. Suchcompounds would have a wide range of uses. Compounds with oily, greasy,or waxy characteristics (in ascending degrees of hardness) can be usedas lubricants of surgical instruments and implants. Applications wouldinclude use as a carrier or excipient for particulate implantablematerials, bioactive agents, and other pharmaceutical agents. Random AOCcompounds are also suitable as a matrix for particulate material,adhesive/cohesive, filler, and/or lubricant; they may also be used asdispersing or suspending agents, emulsifiers, extenders, thickeners,and/or bodying agents for compositions and other pharmaceuticalformulations.

Currently, the medical and surgical need for the appropriateformulations is being met in a number of different and less thanacceptable ways. Most have the problem of either not being completelybiocompatible or not having handling characteristics that are wellsuited for their intended application. Compounds derived from biologicalsources, such as collagen, have the potential to cause immune reactionsand may even have the potential to spread infectious agents. Manycompounds in use fall into the category of hydrogels. Hydrogels ingeneral lack the appropriate handling characteristics in that they lackplasticity, and are often unstable when compressive forces are appliedto them. The water within hydrogels also may affect the long-termstability of pharmaceutical and biological agents. Petroleum-basedhydrocarbon compounds have the appropriate handling characteristics, butare not water soluble. Silicon oils and silicon gels are neitherbiologically inert nor water soluble. Thus, suitable polymers fortherapeutic use remain to be discovered.

In the fields of surgery and dentistry, there is a need for animplantable material that contains a particulate component that canserve as a framework for tissue ingrowth. The particulate component canbe selected from a broad range of natural and synthetic implantablesubstances, including but not limited to native autogenous bone orcartilage, bone or cartilage from other sources that is either grafteddirectly or after processing, collagen, hydroxyapatite,poly-methylmethacrylate (PMMA), polytetrofluoroethylene (PTFE),polyethylene, and dimethylpolysiloxane.

The performance of particulate implants is markedly improved by theaddition of a matrix to temporarily adhere the particles to one anotherand to form a putty that serves to improve the handling characteristicsand acts as a delivery system. The majority of matrices in use ordisclosed in the prior art are hydrogels, and they include collagen,glycerol, polysaccharides, mucopoly-saccharides, hyaluronic acid,plasdones, and polyvinylpyrrolidones (PVP).

Collagen, in the form of gelatin, has been used in ARTEPLAST® from RofilMedical International. It is an injectable material comprised ofmicro-spheres of polymethylmethacrylate (PMMA) suspended in a gelatinsolution. Following implantation, the gelatin is resorbed and replacedby native collagen. Another formulation, ARTECOLL® is a productcurrently available in Europe and Canada. It is comprised of smooth PMMAspheres, suspended in bovine collagen from a closed pharmaceutical herdat a concentration of 25% PMMA/75% collagen, by weight with 0.3%lidocaine. Because ARTECOLL® contains bovine collagen, testing forallergy to such collagen is recommended. Bovine collagen carries therisk of an immunogenic reaction by the recipient patient. Recently, ithas been found that a disease of cattle, bovine spongiformencephalopathy (BSE) is transmitted from bovine tissue to humans. Thus,bovine collagen carries a risk of disease transmission and is not adesirable matrix for allograft bone. Human collagen is free of theseanimal-based diseases. However, collagen absorbs slowly in the humanbody, particularly in a bony site with a low degree of vascularity.

Glycerol is used as a matrix for demineralized allograft bone in theform of a gel. For example, GRAFTON® from Osteotech is a simple mixtureof glycerol and lyophilized, demineralized bone powder (U.S. Pat. No.5,073,373). GRAFTON® works well to allow the surgeon to place theallograft bone at the site. But glycerol has a very low molecular weight(92 daltons) and is very soluble in water, the primary component of theblood which flows at the surgical site. Glycerol also experiences amarked reduction in viscosity when its temperature rises from roomtemperature (typically 22° C. in an operating room) to the patient'sbody temperature (typically 37° C.). This combination of high watersolubility and reduced viscosity causes the allograft bone with aglycerol matrix to be runny and to flow away from the site almostimmediately after placement. This prevents the proper retention of theallograft bone within the site as carefully placed by the surgeon. Theuse of the low-molecular weight glycerol carrier also requires a highconcentration of glycerol to be used to achieve the bulk viscosity.Glycerol and other low-molecular weight organic solvents are also toxicand irritating to the surrounding tissues. U.S. Pat. No. 6,306,418describes the use of glycerol as the matrix for TEFLON® particles in thefield of urology.

Surgical implantation of artificial sphincters has often been employedto treat patients suffering from urinary incontinence. The most commonand widely used method to treat patients with urinary incontinence isperiurethral injection of a composition commercially sold as POLYTEF™,which is a paste comprising a 1:1 by weight mixture of glycerin matrixand TEFLON® particles. After injection, however, the glycerin is readilydissipated into the body over a period of time and then metabolized oreliminated, leaving only the TEFLON® particles. A drawback of such apaste is that the size of the particles is sufficiently small so as toallow them to migrate to other locations of the body such as the lungs,brain, etc. TEFLON® particles have been known to induce tissue reactionand form TEFLON®-induced granulomas in certain individuals. This tissuereaction to TEFLON® also has caused concerns for the patient's health.

U.S. Pat. No. 4,191,747 discloses a bone defect treatment with denaturedbone meal freed from fat and ground into powder. The bone meal is mixedwith a polysaccharide in a solution of saline and applied to the bonedefect site.

U.S. Pat. No. 5,290,558 discloses a flowable, demineralized bone powdercomposition using an osteogenic bone powder mixed with a low molecularweight polyhydroxy compound possessing from 2 carbons to about 18carbons including a number of classes of different sugars such asmonosaccharides, disaccharides, water-dispersible oligosaccharides, andpolysaccharides.

U.S. Pat. No. 5,356,629 discloses making a rigid gel in the form of abone cement to fill defects in bone by mixing biocompatible particlespreferably PMMA coated with polyhydroxyethylmethacrylate in a matrix(e.g., hyaluronic acid) to obtain a molded semisolid mass which can besuitably worked for implantation into bone. The hyaluronic acid can alsobe utilized in monomeric form or in polymeric form preferably having amolecular weight not greater than about one million daltons. It is notedthat non-bioabsorbable but biocompatible particles can be derived fromxenograft bone, homologous bone, autogenous bone, as well as othersubstances. The bioactive substance can also be an osteogenic agent suchas demineralized bone powder, in addition to morselized cancellous bone,aspirated bone marrow, and other autogenous bone sources. This is acement used for implantation of hip prosthesis.

Ersek et al. describe the clinical use of soft particles delivered as abiphasic hydrogel material (Plast. Reconstr. Surg. 95:985-992, 1995).The material comprises solid particles of dimethylpolysiloxane rangingin size from 100 micron to 600 micron suspended in a gel(CHCH₂)₂N(CH₂)₃—CO of the plasdone family.

BIOPLASTIQUE® material from Uroplasty, a biphasic material, consists ofsolid silicone particles, ranging from 100 microns to 400 microns insize, suspended in a polyvinylpyrrolidone (C₆H₉NO)_(n) (PVP). But thismaterial elicits a low-grade inflammatory response upon injection. In arabbit model, the hydro-gel matrix is reabsorbed by the body within 96hours and eliminated in an intact form by the kidneys. The hydrogelmatrix is replaced by fibrin and inflammatory cells. Fibroblasts arerecruited into the area by 14 days and begin to replace the fibrin bedwith a collagen matrix. The collagen encapsulates and localizes thesilicone, and animal studies have not shown any evidence of foreign bodymigration. Deposition of collagen progresses, replacing the organiccomponent of the material in a ratio slightly greater than 1:1.Connective tissue cells develop and replace about 30% of the matrix withhost collagen fibrils. At 382 days, fibrosis was complete and eachindividual particle appeared to be encased in its own fibrous capsule.This material has the distinct disadvantage of using silicone, which maybe of concern when evaluating long-term safety.

U.S. Pat. No. 5,641,502 discloses a material comprising (i) a polymerderived from hydroxyacids, tactones, carbonates, etheresters,anhydrides, orthoesters, and copolymers, terpolymers and/or blendsthereof and blended with (ii) at least one surface active agent which isfrom 2% to 55% by weight block copolymer of polyoxyethylene andpolyoxypropylene. Additionally, a leaching agent from 1% to 70% byweight may be included in the blend to provide a porous microstructure.

U.S. Pat. No. 6,281,195 discloses a poloxamer hydrogel matrix for thedelivery of osteogenic proteins. In particular, poloxamer 407 (PLURONIC®F127) is used in the form of a hydrogel. But hydrogels havedisadvantages if used as the matrix instead of the present composition.

Therefore, it is an objective of the invention to provide a compoundwith superior properties for medical and surgical applications. Handlingproperties, biocompatibility, lubricity, non-toxicity, and tackiness arecharacteristics which are of particular interest. Further advantages ofthe invention are described.

SUMMARY OF THE INVENTION

The invention relates to a random alkylene oxide copolymer (random AOC)that can be advantageously used in medicine, surgery, and various othertherapeutic applications. This compound is a random copolymer comprisedof ethylene oxide and one or more other alkylene oxide(s), wherein therandom copolymer has (i) molecular mass from 1 kg/mol to 1000 kg/mol(the average mass of the distribution of copolymers) and (ii) mass ratioof the ethylene oxide to the other alkylene oxide is from 5:95 to 95:5.Compositions may contain at least random AOC, and optionally one or moretherapeutic products.

The random AOC can be biocompatible and substantially non-toxic toliving tissue. Under physiological conditions, it can be substantiallystable such that it is not metabolized and is readily eliminated fromthe body in unmodified form. The random AOC can be water soluble, but itmay also be formulated to contain no water (i.e., substantiallyanhydrous except for minor amounts of absorbed water). Water may beadded prior to use or absorbed in the body. But it is preferred toformulate the compound as a flowable liquid (with less than 5% or 1%water) before use in the body or further formulation. Generally, it isnot considered a hydrogel, especially before use in the body or furtherformulation.

Choice of the other alkylene oxide(s), molecular mass, mass ratio, andprocedures during manufacture can affect the compound's properties:e.g., hardness, adhesiveness, cohesiveness, ductility, malleability, andhardness. For example, “working” the compound or composition maystabilize these properties by homogenizing its internal structure.Handling characteristics may be similar when compared between ambienttemperature (e.g., 20° C. to 25° C.) and body temperature (e.g., 37° C.or 40° C.).

Such products may be administered to the body (e.g., applied topicallyto the skin or other exposed tissue, depot or suppository, implanted orplaced therein, ingested, injected). Biocompatibility and non-toxicityare desirable properties for such applications.

A matrix product is provided in some embodiments which is comprised of:(i) solid or porous particles suspended in (ii) a random AOC compound ora composition thereof. This matrix material may be adhered to hardtissues (e.g., tooth, bone, cartilage) and other body tissues withminimal adverse reaction by the tissue (i.e., biocompatible). The matrixmay be eliminated with time to leave behind a framework of theparticles, and tissue may grow within the framework. Other polymers mayalso be formulated with the random AOC.

Further objectives are to provide compounds, compositions, and otherproducts for use in medical and surgical applications. They may beinserted into a body cavity or tissue, placed adjacent to mucosa as asuppository, or administered orally, parenterally, or topically. Theycan be used as carriers or excipients for bioactive agents,adhesives/cohesives, detergents, lubricants, and particulate matrices.In addition to hemostasis and tissue augmentation, a bioactive agent maybe delivered or a bioimplant may be manufactured.

In another embodiment, a random AOC may be used as an excipient forother surgical and medical applications. The excipient may takeadvantage of any one of the beneficial properties described herein todeliver a therapeutic (e.g., bioactive agent or device) in the body of ahuman or animal. For example, the excipient may act as a lubricant toassist the passage or placement of the therapeutic in the body or a partthereof. Such pharmaceutical compositions may also include a vehicle(e.g., water, physiological saline, buffered solution). Processes forusing and making the excipient and composition are also provided.

Further aspects of the invention will be apparent to a person skilled inthe art from the following detailed description and claims, andgeneralizations thereto.

DESCRIPTION OF SPECIFIC EMBODIMENTS OF THE INVENTION

Compounds and compositions of the present invention may be utilized fora wide variety of medical and surgical applications. The discovery thata family of random AOC compounds can be used in therapy was surprisingand unexpected. Such uses are described in more detail below.

Random AOC may be applied as a carrier to a device (e.g., polyethyleneimplant or metal instrument) to improve its handling and to alter thesurface characteristics of the device. Another embodiment is a randomAOC matrix and a porous or solid filler for use in surgery. The matrixcan also act as a flowable, anhydrous, biocompatible, non-toxic, and/oradhesive system with characteristics desirable for safe and effectivedelivery of bioactive agents (e.g., malleable at room temperature andreadily eliminated from the body). In growth of tissue may be promotedwith a porous network left behind by resorbed matrix. Cosmetic andreconstructive surgery may use random AOC for augmentation, adheringbody parts and/or surgical device/instrument, temporarily attachingtissue until permanent adhesives are activated, and/or for lubrication.

Poly(alkylene oxide)s (PAO) which are also known as polyoxyalkylenes(POA) are made by the polymerization of alkylene oxides (e.g., ethyleneoxide, propylene oxide, butylene oxide). A homopolymer is formed onlyfrom one type of alkylene oxide while a copolymer is formed from two ormore different alkylene oxides, known as alkylene oxide copolymers(AOC). Examples of the former are poly(ethylene oxide) (PEO), which is apolymer of ethylene oxide (EO), and poly(propylene oxide) (PPO), whichis a polymer of propylene oxide (PO). Poly(ethylene oxide) is alsocommonly known as polyethylene glycol (PEG) or polyoxyethylene (POE).Molecular weight of such polymers is generally characterized as theaverage of a distribution of lengths (or repeat units). PEO isamphiphilic, extremely hydrophilic, water soluble, biocompatible, andnon-toxic and is produced commercially in a wide range of molecularweights (200 g/mol to 10 million g/mol). Low-molecular weight forms ofPEO below 600 g/mol (i.e., oligomeric forms with less than 14 EO monomerunits on average) are low-viscosity liquids at room temperature; PEO isa solid at 25° C. above 600 g/mol. PPO differs from PEO in that it ishydrophobic, generally insoluble in water except at low molecularweights (less than about 1 kg/mol), and is liquid at 25° C. even at highmolecular weights (e.g., 6 kg/mol).

In addition to the standard linear forms, branched or star forms ofpoly(alkylene oxide)s are produced by initiating the polymerizationreaction with a polyfunctional initiator with multiple hydroxyl-,amino-, or thiol-groups each of which can serve as a starting point forpolymer chain growth. For example, the use of glycerol (three hydroxylgroups) as an initiator results in a three-armed branched polymer, whilepentaerythritol results in a four-armed polymer. PEO molecules of thistype are available commercially (e.g., the Sunbrightm series, NOFCorporation, Japan) with anywhere from three to more than one hundredarms. Conventionally, polymers of this type with 3 to 10 arms are termed“branched” while those with more than 10 arms are termed “star”polymers. “Comb” copolymers are similar to branched and star forms, butthe initiator for comb copolymers is a polyfunctional polymer withmultiple hydroxyl-, amino-, or thiol-groups spaced along the initiatorbackbone, each of which can serve as a staring point for polymer chaingrowth. “Graft” copolymers are made by the addition of pendant polymerchains along a polymer backbone that possesses unsaturated C═C bonds orpendant functional groups (e.g., hydroxyl) from which pendant chains canbe added by using a reactive monofunctional polymer chain.

All poly(alkylene oxide)s contain, in addition to multiple alkyleneoxide-derived repeat units, a single residue corresponding to themolecule used to initiate the polymer synthesis. For linear polymers,this may be an alkylene glycol corresponding to the alkylene oxide usedfor the synthesis (e.g., ethylene glycol and ethylene oxide,respectively) and thus the initiator-derived residue will beindistinguishable from the other repeat units in the polymer chain. Butsmall molecules other than alkylene glycols are often used asinitiators, examples include methanol or N-butanol (for linear polymers)and trimethylol propane, glycerol, or pentaerythritol (for branchedpolymers). The mass of initiator relative to the mass of the finalpolymer chain is generally very small and can usually be neglected.Thus, the term poly(alkylene oxide) is used here in its customary sense,and includes both poly(alkylene oxide)s initiated with an alkyleneglycol molecule and poly(alkylene oxide)s initiated with another smallmolecule.

Random AOC preferably has a molecular mass from about 1 kg/mol to about1000 kg/mol (i.e., average molecular mass of a distribution ofpolymers). It may have a molecular mass of at least about 5 kg/mol,about 10 kg/mol, or about 20 kg/mol; the molecular mass may also be notmore than about 25 kg/mol, about 50 kg/mol, or about 200 kg/mol. Themass ratio of ethylene oxide to the other alkylene oxide(s) preferablyis from about 5:95 to about 95:5. It may have a mass ratio of at leastabout 10:90, about 25:75, or about 40:60; the mass ratio may also be notmore than about 60:40, about 75:25, or about 90:10. The compounds may bedescribed by intermediate ranges using the aforementioned upper andlower limits.

In a particular embodiment, the molecular mass may be from about 15kg/mol to about 30 kg/mol. Preferably, the molecular mass is at leastabout 20 kg/mol and/or not more than about 25 kg/mol and the mass ratioof ethylene oxide to propylene oxide is substantially equimolar. RandomEO/PO copolymers have a certain combination of properties whichdistinguish them from EO and PO homopolymers and EO/PO block copolymers,and which make them uniquely useful as excipients for certainpharmaceutical applications. The most important of these is that theycombine two of the desirable properties of PEO and PPO - i.e., they areliquids at room temperature and above over a wide range of molecularweights, but are water soluble. In contrast, except at low molecularweights (less than 1 kg/mol), PPO is not water soluble and PEO is asolid. Also, unlike most block copolymers, random EO/PO copolymers donot self-associate to form structured domains or a crystalline structure(hence their liquid nature), and they are therefore useful as solventsor softeners for a wide range of other polymers and copolymers.

Like all other PAOs, they are soluble in selected organic solvents, ableto solubilize many organic and inorganic substances includinghydrophobic drugs that are insoluble or poorly soluble in water, and aresubstantially non-toxic.

Water-soluble PAO have low toxicity when applied to the skin or takenorally. There is some evidence that small PEG molecules (600 g/mol orless) may be metabolized in vivo to produce oxalate, which is toxic. Butlarger PAO are known to be effectively inert and non-metabolizable invivo, and are excreted in substantially unmodified form. This provides afurther advantage of the higher molecular weight random PAO liquids vs.liquid PEG.

Random EO/PO copolymers are non-aqueous flowable liquids and inert, butwater soluble. They can be used in anhydrous formulations which areuseful for when water is undesirable. Random EO/PO copolymers aremiscible with other poly(alkylene oxide)s and more desirable in thisregard than a liquid poloxamer. In summary, random EO/PO copolymersoffer unique, novel, and unanticipated benefits when used aspharmaceutical excipients, especially in formulations for parenteraluse. When appropriately selected for molecular weight, geometry, andEO:PO ratio, such random copolymers are versatile and advantageousalternatives to low molecular weight liquid PEO and PPO and somepoloxamers as an excipient for drug formulations; can replaceemulsifiers for preparation of formulations of some hydrophobic drugs;can solubilize certain hydrophobic drugs in the complete absence ofwater; are a unique excipient for plasticizing, softening, orsolubilizing other materials in the absence of water or other smallmolecule solvents (e.g., when the presence of water or solvent isundesirable); and when used in combination as a blend, will furthermodify and extend the properties of polymers, making them more useful asexcipients in general, and in particular as carriers for delivery ofbioactive agents or as implantable carriers for particulate materials.

This combination of properties distinguishes random EO/PO copolymersfrom most other polymeric liquids including EO or PO homopolymers andblock copolymers as follows:

1. Low molecular weight liquids (e.g., glycerol, PEG of 600 gimol orless) generally dissolve very rapidly in water, have low viscosity,readily leach out of formulations, and have a very high osmoticpotential due to their low molecular weight. In contrast, random EO/POcopolymers are liquid over a larger molecular weight range, their rateof dissolution and viscosity can be selected for by choosing the EO:POratio and molecular weight, and their osmotic contribution willgenerally be low (due to the much higher molecular weight).

2. High molecular weight liquids (e.g., PPO) are not water soluble. Incontrast, random EO/PO copolymers are water soluble and will be resorbedfrom the site of administration at a rate that can be predicted basedupon the EO:PO ratio and molecular weight.

3. The random structure does not self associate, and most random EO/POcopolymers are water clear liquids above their melting point, unlikemany poloxamers that are liquid at room temperature (e.g., poloxamer-124or PLURONIC® L44), which range from turbid liquids to liquid pastes.

A preferred embodiment uses a branched or linear random alkylene oxidecopolymer with a molecular weight of about 22,000 daltons (22K randomAOC). Such a compound is commercially available from BASF Corporation asPLURACOL® V-10 (V-10). According to its manufacturer, V-10 was developedspecifically for use in water-glycol fire-resistant hydraulic fluids andis additionally suitable as a water-soluble, cutting and grinding fluidand in various metal working applications. Furthermore, the manufacturerdiscloses that complete toxicity information on V-10 has not yet beenfully developed and that the normal precautions exercised when handlingany chemical should be used when working with V-10: e.g., eye protectionshould be used and prolonged contact with the skin should be avoided.The discovery that random AOC are useful for medical and surgicalapplications is novel and inventive.

Random AOC are produced by several manufacturers including BASF, DowChemical, and Sigma/Aldrich under the trade names PLURADOT®, PLURACOL®,SYNALOX® EPB, and EMKAROX® among others. They are available in a rangeof EO:PO ratios and molecular weights (e.g., 1 kg/mol to 22 kg/mol) andin linear and branched geometries, and are commonly characterized bytheir viscosity rather than molecular weight. Dow Chemical provides anumber of random AOC with molecular weights in the range of 1,500 to4,900 including those with the following codes: EP 530, EP 1730, EP 435,EP 1660, 15-200,112-2, UCON 50-HB-5100, and UCON 50-HB-660.Sigma/Aldrich provides a number of random AOC with molecular weights inthe range of 2,500 to 12,000 including those with the following codes:43,819-7, 43,820-0, 43,818-9,40,918-9. Medical applications for PAO havebeen focused on block AOC. In contrast, the use of random AOC has almostexclusively been restricted to non-medical applications, and theirpotential for providing medical benefits has been largely overlooked.

Implants used in humans and animals may be manufactured by sinteringsolid particles such as polyethylene, methylmethacrylate, or titanium;or they are adapted from naturally substances such as coral in the caseof porous coralline hydroxyapatite. Polyethylene, a biologically inertmaterial, has numerous applications in surgery; it is a straight-chainhydrocarbon made by polymerizing ethylene. Hydroxyapatite and tricalciumphosphate are similar in composition to the major mineral component ofbone and may be resorbed or remodeled, depending on their formulation.Methacrylate- and silicone-containing particles are not preferred.

Placement of implants into one or more bone defects is a common surgicalprocedure. Implant materials that allow for bone to grow into the poresare considered to be osteoconductive. Implants that have a bioactivecomponent that induce bone formation, such as implants made from a boneremoved from a different location, are considered to be osteoinductive.In the event that it is desirable that native bone eventually replacesthe implant, material that can be remodeled by the body may bepreferable. In certain clinical situations, such as a defect in theadult human cranium, the bone is not expected to grow, and anon-resorbable formulation is preferable. Studies have shown that in thecraniofacial skeleton, a number of commonly used solid implants causebone resorption adjacent to the site of implantation. Porous implantsmay not have the same effect.

The majority of porous implants that allow for tissue in growth aregrossly solid structures with a microporous structure. To be clinicallyuseful, they often need to be sculpted by the surgeon into their desiredform. The microporous structure of the implant can cause the implant toadhere to tissue, much like a piece of Velcro, making the implantplacement difficult. Debris deposition into the pores is anotherundesirable drawback to the use of porous implants. To decrease the riskof bacterial infection, the implant may be soaked in an antibioticsolution prior to use.

An implant whose pores are filled with a biocompatible excipient wouldbe an improvement over the implants in current clinical use. Temporarilyfilling those pores until such time as in growth of tissue occurs wouldeliminate the accumulation of debris within the implant and coulddecrease the incidence of bacterial infection. Temporarily filling thepores using an appropriate excipient would also improve its handlingcharacteristics to make the implant more lubricious and less damaging totissue, thus allowing the implant to slide along tissue planes duringsurgical placement. The appropriate excipient could then also becomeadherent in the presence of body fluids and lessen the incidence ofmalpositioning that can occur after implant placement. The biocompatibleexcipient could also serve as a carrier for therapeutic products. Forexample, chemical compounds could be released over time as the excipientis resorbed.

The compound may be biocompatible and substantially non-toxic, have astable shelf life, be relatively economic, and have superior handlingcharacteristics. A carrier should allow the implant to be lubricious toglide along tissue planes, but it should also enable the implant tobecome adherent to surrounding structures when its final position isattained. Cohesion may be used to temporarily hold tissue together untilmore permanent attachments may be made. An anhydrous formulation wouldincrease stability for the long term and reduce the risk ofcontamination.

In a number of clinical applications, it is advantageous to construct aporous structure by placing an aggregate of solid particles or granulesthat become fixed in into their desired location by the in growth ofsoft tissue into the spaces between the particles. Allograft bone is asubstitute source for solid particles. It is readily available andprecludes the surgical complications and patient morbidity associatedwith autologous bone as noted above. Allograft bone may be considered acollagen fiber reinforced hydroxyapatite matrix containing active bonemorphogenic proteins (BMP) and can be provided in a sterile form. Themineral component may be removed from bone to form a demineralized bonematrix (DBM). Such DBM is naturally both osteoinductive andosteoconductive. Once surgically implanted, DBM is fully incorporated inthe patient's tissue and it has been used in bone surgery to fillosseous defects. DBM is usually available in a lyophilized orfreeze-dried and sterile form to provide for extended shelf life. TheDBM in this form is usually very coarse and dry, and is difficult tomanipulate by the surgeon. It is known that DBM can be supplied in amatrix of low molecular weight solvents, but these are know to be toxicto the surrounding tissue, and they form a runny composition. DBM isusually available in a lyophilized or freeze-dried and sterile form toprovide for extended shelf life. The bone in this form is usually verycoarse and dry, and is difficult to manipulate by the surgeon. It isknown that DBM can be supplied in a matrix of low molecular weightsolvents, but these are know to be toxic to the surrounding tissue, andthey form a runny composition.

Inorganic materials can also provide a matrix for new bone to grow atthe surgical site. These inorganic materials include hydroxyapatiteobtained from sea coral or derived synthetically. Either form may bemixed with the patient's blood and/or bone marrow. Hydroxyapatitegranules may be used as bone inlays or onlays. The granules can be mixedwith microfibrillar collagen and blood from the patient.

Particles with sizes (i.e., the largest dimension) in the range fromabout 35 microns to about 500 microns (or about 50 microns to about 150microns) are desirable to minimize the possibility of particle migrationby phagocytosis and to facilitate injectability. Phagocytosis occurswhere smaller particles on the order of 15 microns or less becomeengulfed by the cells and removed by the lymphatic system from the sitewhere the augmentation material has been introduced into the tissues,generally by injection. At the lower end, particles greater than 15microns (typically 35 microns or above) are too large to bephagocytosed, and can be easily separated by known sizing techniques(e.g., filtration, gel exclusion, molecular sieving). For a populationof substantially spherical particles, the diameter may range from about35 microns to about 500 microns for at least the majority of thepopulation. Thus, it is relatively simple to produce narrow orequivalent particle size ranges that are desirable for use.

Particles may comprise at least about 10% (v/v), at least about 25%(v/v), not more than about 40% (v/v), not more than about 64% (v/v), orcombinations thereof. The composition may be kneaded or otherwise workedto obtain a homogeneous distribution of particles within a randomAOC-containing composition. Such working is avoided, however, if anon-homogeneous distribution is desired and different compositions mayeven be laminated together.

Excipients are biologically inactive substances that are associatedwith, often in combination, drugs, devices, and other therapeutic agentsto make a therapeutic product. They may be classified by the function(s)they perform as binders, disintegrants, fillers, diluents, dispersing orsuspending agents, lubricants, flow enhancers, softeners, plasticizers,and coatings. Although biologically inert, they may be critical andessential components of a therapeutic product. They can be used toenhance drug stability and bioavailability or to control the locationand rate of release of the drug. They also may be required to deliver apharmaceutical formulation by a desired route, whether oral, parenteral,enteral, or topical and, if appropriate, to enhance the appearance andpalatability of the product. In many therapeutic products, excipientsmake up the bulk of the total dosage form. The excipient can besterilized prior to formulation by autoclaving or irradiation, or theformulation may be sterilized as part of its production. In addition, avehicle may be included in the therapeutic product. It may be water,another aqueous solution with a buffer and/or physiological salts,non-aqueous solution, emulsion, or suspension. The device may be afiller, anchor, catheter, implant, plate, prosthesis, screw, suture,surgical instrument, or the like; it may be made from bone (e.g., chipsor powder) or a derivative thereof (e.g., demineralized bone), ceramic(e.g., calcium salt especially hydroxyapatite), glass, polyethylene, ormetal (e.g., stainless steel, titanium). The drug may be a bone growthfactor or morphogenic protein, hormone, other protein, nucleic acid(e.g., DNA, RNA, analogs or mixtures thereof, analgesic or anesthetic,antibiotic, anti-septic, narcotic, steroidal or nonsteroidalanti-inflammatory agent, or the like.

Random AOC compounds are also well suited as carriers or excipients fordelivery of bioactive agents, medical/surgical devices (e.g., implantsand instruments), and other therapeutic (e.g., non-polymeric) products.Articles may be coated with carrier or chemicals may be mixed withexcipient. Sterilization may be performed in an autoclave or byirradiation for use in vivo.

Bone morphogenic proteins (BMP) and TGF-beta are two examples ofbioactive substances. Other differentiation factors, stem cell factors,antibiotics, antibodies, antigens, chemotherapeutics,cytokines/chemokines, enzymes and their substrates (e.g., activators,inhibitors, or reactants), receptors (especially secreted forms andmimetics thereof) or their ligands (e.g., agonists or antagonists),signaling molecules (e.g., mediators of a signal transduction pathway,agonists or antagonists thereof) may be formulated in a composition withrandom AOC.

As a carrier or excipient, the compound's attributes of being at leastbiocompatible, substantially non-toxic, simple to manufacture,substantially non-metabolizable and readily eliminated by a human oranimal are important. In addition, random AOC may act to solubilizehydrophobic substances and release them into solution. An anhydrousformulation has the benefit of providing a stable excipient to thosebioactive agents that are not stable in an aqueous environment.Furthermore, if water is present, the random AOC serves to bind thewater to make it unavailable to interact with the bioactive agent.

In further embodiments, random AOC compounds and random AOC-containingcompositions may be used as lubricant and/or detergent.

During surgery, lubrication of instruments or other devices is usuallylimited to physiological saline and the patients own fluids. Use oflubricious substances derived from human or animal sources risks animmune response and the transmission of infectious agents. There is aneed for a safe, biologically inert, inexpensive substance that could beused as a surgical lubricant that can be applied when needed. Such alubricant could decrease tissue injury and/or improve the handlingcharacteristics of devices as they are passed through tissue. Examplesof injuries caused by surgical instruments are abrasive tissue burnscaused by endoscopic instruments as they are moved along narrow tissueplanes. Surgical implants, such as those made from porous polyethylene,are especially difficult to pass along tissue planes, since soft tissuetends to adhere to these implants. Breast implants, especially thosewith a textured surface that are placed through small, remote incisions,can be very difficult to place without sufficient lubrication.

Surgical instruments require that they be cleaned prior to use insurgery. The compounds and compositions disclosed here may be used asinstrument milk within a cleaning apparatus for the cleaning of surgicalinstruments. The random AOC may be used as a detergent.

Joints of some surgical instruments (e.g., scissors and clamps)typically need to be cleaned and the joints need lubrication. Suchinstruments are dipped in instrument milk prior to their use in surgery.Thus, in addition to the aforementioned use as a detergent, the randomAOC may be used as a lubricant.

The effectiveness of random AOC as instrument milk may be enhancedbecause of its biocompatibility, flowability, non-toxicity, and watersolubility.

In another embodiment of the invention, random AOC compounds and randomAOC-containing compositions may be used to clean and/or lubricateimplantable devices.

As described above, random AOC can be used as an excipient for drugdelivery or in the manufacture of other bioactive agent-containingcompositions to deliver such compounds to a subject though a variety ofroutes, including percutaneous, enteric, intranasal or respiratory,topical, and through mucous membranes (e.g., rectum). When ingestedorally in sufficient quantity, random AOC may have biological activityof its own due to the ability to draw water into the gastrointestinaltract and act as a laxative.

There are a variety of topical formulations encompassing creams, gels,and ointments, including sun blocks and wound dressings. There is anunmet need for a lubricious component which absorbs water and is thusbeneficial in treating seeping wounds and stasis ulcers. Random AOC maybe packaged in a bottle or tube, applied to the wound, and thenoptionally covered by a occlusive or non-occlusive dressing.Alternatively, the compound may be prepackaged with the dressing underaseptic conditions.

Therefore, in some embodiments, random AOC compounds and randomAOC-containing composition may be used as a laxative or wound dressing.

EXAMPLES

The following examples more particularly describe the invention but areintended for illustrative purposes only, since modifications andvariations will be apparent to those skilled in the art.

Example 1 Non-Toxicity of Random AOC

The biocompatibility of a random AOC (22K random AOC) was demonstratedby assessing intracutaneous reactivity, systemic toxicity, andcytotoxicity.

The 22K random AOC was evaluated for intracutaneous reactivity to testfor potential irritation and sensitization. A 0.2 ml dose of thematerial was injected by the intracutaneous route into five separatesites on the backs of rabbits, along with controls. Observations forerythema and edema were conducted at 24, 48, and 72 hours afterinjection showed no evidence of irritation. The primary irritation indexcharacterization for the 22K random AOC was negligible.

The 22K random AOC was evaluated for systemic toxicity in accordancewith the guidelines of the United States Pharmacopoeia and theInternational Organization for Standardization (ISO) 10993. A single 25mvkg body weight dose of the material was injected into mice by theintravenous route. The animals were observed at timed intervals for 7days without any evidence of systemic toxicity.

Cytotoxicity was assessed using an in vitro biocompatibility study basedon ISO 10993. A solution was prepared supplemented with 5% serum and 2%antibiotics, placed over confluent monolayers of L-929 mouse fibroblastcells propagated in 5% CO₂, and incubated at 37° C. in the presence of5% CO₂ for 48 hours. The monolayers were examined microscopically at 48hours and showed no evidence of a change in cell morphology, cell lysis,or cell toxicity.

Example 2 Random AOC is Readily Eliminated

The in vivo elimination of a random AOC (22K random AOC) was studied ina rat model. The urinary and fecal elimination of ³H-labeled 22K randomAOC from adult Sprague-Dawley rats was determined. Each rat was injectedsubcutaneously with 10 mg of [³H]22K random AOC with a radioactivity of50 μCi. Rats were housed individually in stainless steel metabolismcages after injection; urine and feces were collected at 24-hour timeintervals over a 168-hour period. The radiolabeled 22K random AOC waspredominantly excreted in the rats' urine (about 60% to about 80%), withthe remainder excreted in their feces. Most of the radiolabel (about 55%to about 70%) was excreted within the first 24 hours after injection.

Example 3 Biocompatible Cleanser

The utility of random AOC compounds as detergents may be assessed. Theirsurfactant activity and ability to remove stains or contaminants fromthe surface of a device or instrument can be compared to otherdetergents used in clinical settings. Viscous compositions containingrandom AOC may be used in situations where the cleanser is intended toadhere to the surface in need of deep cleansing; otherwise, non-viscouscompositions may be used for quick washing and rinsing. Biocompatibilityof random AOC would be advantageous because of the ease with which thecleaned device or instrument re-enters use in the clinic. This is analternative to harsh detergent cleansers.

Example 4 Non-Corrosive Lubricant

The utility of random AOC compounds as lubricants may be assessed. Theirability to make a medical device, surgical implant, or instrumentslippery can be compared to other lubricants used in clinical settings.Compositions containing random AOC of varying viscosity (e.g., oil togrease) may be used depending on the situation. The biocompatibility ofrandom AOC and its rapid elimination would be advantageous because ofthe compound's safety.

Example 5 Delivery of Bioactive Agent

A bioactive agent (e.g., carbohydrates, lipids, natural products andsynthetic analogs thereof, nucleic acids, small molecules synthesized byman, proteins, antibiotics, antibodies, antigens, chemotherapeutics,imaging and contrast agents, radiotherapeutics, receptors or theirligands) may be formulated with a random AOC (22K random AOC). Thecirculation of the bioactive agent in the body and its elimination, thecatabolism of the bioactive agent, and safety and effectiveness oftherapy may be compared to aqueous solutions and compounds known toassist in the solubilization of hydrophobic molecules.

Patents, patent applications, books, and other publications cited hereinare incorporated by reference in their entirety.

In stating a numerical range, it should be understood that all valueswithin the range are also described (e.g., one to ten also includesevery integer value between one and ten as well as all intermediateranges such as two to ten, one to five, and three to eight). The term“about” may refer to the statistical uncertainty associated with ameasurement or the variability in a numerical quantity which a personskilled in the art would understand does not affect operation of theinvention or its patentability.

All modifications and substitutions that come within the meaning of theclaims and the range of their legal equivalents are to be embracedwithin their scope. A claim using the transition “comprising” allows theinclusion of other elements to be within the scope of the claim; theinvention is also described by such claims using the transitional phrase“consisting essentially of” (i.e., allowing the inclusion of otherelements to be within the scope of the claim if they do not materiallyaffect operation of the invention) and the transition “consisting”(i.e., allowing only the elements listed in the claim other thanimpurities or inconsequential activities which are ordinarily associatedwith the invention) instead of the “comprising” term. Any of these threetransitions can be used to claim the invention.

It should be understood that an element described in this specificationshould not be construed as a limitation of the claimed invention unlessit is explicitly recited in the claims. Thus, the granted claims are thebasis for determining the scope of legal protection instead of alimitation from the specification which is read into the claims. Incontradistinction, the prior art is explicitly excluded from theinvention to the extent of specific embodiments that would anticipatethe claimed invention or destroy novelty.

Moreover, no particular relationship between or among limitations of aclaim is intended unless such relationship is explicitly recited in theclaim (e.g., the arrangement of components in a product claim or orderof steps in a method claim is not a limitation of the claim unlessexplicitly stated to be so). All possible combinations and permutationsof individual elements disclosed herein are considered to be aspects ofthe invention. Similarly, generalizations of the invention's descriptionare considered to be part of the invention.

From the foregoing, it would be apparent to a person of skill in thisart that the invention can be embodied in other specific forms withoutdeparting from its spirit or essential characteristics. The describedembodiments should be considered only as illustrative, not restrictive,because the scope of the legal protection provided for the inventionwill be indicated by the appended claims rather than by thisspecification.

1. A compound for use in medicine or surgery, wherein said compound is arandom copolymer comprised of ethylene oxide and one or more otheralkylene oxide(s) having (i) molecular mass from 1 kg/mol to 1000 kg/moland (ii) mass ratio of the ethylene oxide to the other alkylene oxidesis from 5:95 to 95:5.
 2. The compound according to claim 1, wherein saidcompound can adhere to bone, skin, or other body tissue.
 3. The compoundaccording to claim 1, wherein said compound is biocompatible andsubstantially non-toxic.
 4. The compound according to claim 1, whereinsaid compound is substantially not metabolizable and readily eliminatedin unmodified form.
 5. The compound according to claim 1, wherein saidcompound is water soluble but is in substantially anhydrous form.
 6. Thecompound according to claim 1, wherein said compound is not formulatedwith water.
 7. The compound according to claim 1, wherein said compoundis a flowable liquid at 25° C.
 8. The compound according to claim 1,wherein said other alkylene oxide(s) is propylene oxide and/or butyleneoxide.
 9. The compound according to claim 1, wherein said compound isfurther blended with particles and/or at least one other polymer. 10.The compound according to claim 1, wherein said random copolymer has amolecular mass of at least 5 kg/mol.
 11. The compound according to claim1, wherein said random copolymer has a molecular mass of at least 10kg/mol.
 12. The compound according to claim 1, wherein said randomcopolymer has a molecular mass of at least 20 kg/mol.
 13. The compoundaccording to claim 1, wherein said random copolymer has a molecular massof not more than 25 kg/mol.
 14. The compound according to claim 1,herein said random copolymer has a molecular mass of not more than 50kg/mol.
 15. The compound according to any claim 1, wherein said randomcopolymer has a molecular mass of not more than 200 kg/mol.
 16. Thecompound according to claim 1, wherein said other alkylene oxide(s) ispropylene oxide, and said random copolymer has (i) a molecular mass from15 kg/mol to 30 kg/mol and (ii) a mass ratio of the ethylene oxide tothe propylene oxide from 25:75 to 75:25.
 17. The compound according toclaim 16, wherein said random copolymer has a molecular mass from 20kg/mol to 25 kg/mol.
 18. The compound according to claim 16, whereinsaid random copolymer has a mass ratio of the ethylene oxide to thepropylene oxide from 40:60 to 60:40.
 19. A composition for use inmedicine or surgery, which is comprised of (i) at least one bioactiveagent, medical/surgical device, or other therapeutic product and (ii)carrier or excipient comprised of the compound of any one of claims 1 18claim
 1. 20. A process for medically or surgically treating a subject,which comprises: (a) providing the composition of claim 19, and (b)administering said compound or said composition to the subject.
 21. Theprocess according to claim 20, wherein said composition is administeredat least orally, parenterally, or topically to the subject.
 22. Theprocess according to claim 20, wherein said composition is administeredas a suppository to the subject's mucosa.
 23. The process according toclaim 20, wherein said composition is administered during surgery byinsertion into a body cavity or tissue of the subject.
 24. The processaccording to 20, wherein said composition is used as adhesive, cohesive,filler, lubricant, or any combination thereof for medical or surgicaltreatment of the subject.
 25. A process of making a product, whichcomprises combining (a) at least one bioactive agent, medical/surgicaldevice, or other therapeutic product with (b) the compound of claim 1.26. A product made by the process according to claim
 25. 27. Use of theproduct of claim 26 in a medical or surgical application.
 28. A productuseful for medicine or surgery, which comprises (i) particles suspendedin (ii) the compound of any claim
 1. 29. The product of claim 28,wherein said particles are from 10% by volume to 64% by volume.
 30. Theproduct of claim 28, wherein said particles have a size from 35 micronsto 500 microns.
 31. The product of claim 28, wherein said particles areselected from the group consisting of bone chips or powder,demineralized bone, hydroxyapatite, polyethylene, and any combinationthereof.
 32. A process of making a product useful for medicine orsurgery, which comprises suspending (a) particles in (b) a carriercomprised of ethylene oxide and at least one other alkylene oxide having(i) molecular mass from 1 kg/mol to 1000 kg/mol and (ii) mass ratio ofthe ethylene oxide to the other alkylene oxide is from 5:95 to 95:5. 33.A product made by the process according to the process of claim
 32. 34.Use of the product of claim 33 in a medical or surgical application. 35.A process for medically or surgically treating a subject, whichcomprises: (a) providing the compound of claim 1, and (b) administeringsaid compound to the subject.